1. Field of the Invention
The present invention describes novel N-(acyldipeptidyl)-aminoglycols which inhibit human renin.
The present invention is also concerned with pharmaceutical compositions containing the novel glycols of the present invention as active ingredients, and with diagnostic methods which utilize the novel glycols of the present invention.
Renin is a proteolytic enzyme of molecular weight about 40,000, produced and secreted by the kidney. It is secreted by the juxtaglomerular cells and acts on the plasma substrate, angiotensinogen, to split off the decapeptide angiotensin I, which is converted to the potent pressor agent angiotensin II. Thus, the renin-angiotensin system plays an important role in normal cardiovascular homeostasis and in some forms of hypertension.
In the past, attempts to modulate or manipulate the renin-angiotensin system have met with success in the use of inhibitors of angiotensin I converting enzyme. In view of this success, it is reasonable to conclude that a specific inhibitor of the limiting enzymatic step that ultimately regulates angiotensin II production, the action of renin on its substrate, would be at least equally successful. Thus, an effective inhibitor of renin has been long sought as a therapeutic agent, as an investigative tool, and as a diagnostic agent.
2. Description of the Prior Art
There has been a substantial interest in the synthesis of useful renin inhibitors for many decades; the following are the major classes of compounds which inhibit renin in vitro: renin antibodies, pepstatin and its analogs, phospholipids, analogs of angiotensinogen, pro-renin related analogs, and peptide aldehydes.
Umezawa et al., in J. Antiobiot. (Tokyo) 23: 259-262, 1970, reported the isolation of a peptide from actinomyces that was an inhibitor of aspartyl proteases such as pepsin, cathepsin D, and renin. This peptide, known as pepstatin, was found by Gross et al., Science 175: 656, 1971, to reduce blood pressure in vivo after the injection of hog renin into nephrectomized rats. However, pepstatin has not found wide application as an experimental agent because of its limited solubility and its inhibition of a variety of other acid proteases in addition to renin. Thus, investigators have synthesized modified pepstatins in an attempt to increase the specificity for human renin versus other physiologically important enzymes. Unfortunately, while some degree of specificity has been achieved, this approach has led to rather high molecular weight hepta- and octapeptides [Boger, et al., Nature 303, 81 (1983)]; high molecular weight peptides are generally considered undesirable as drugs because gastrointestinal absorption is impaired and plasma stability is compromised. The present invention relates to the use of low molecular weight dipeptide glycols.
Recently, Kokubu et al. BBRC, 118, 929 (1984), and Castro et al., FEBS LETT., 167, 273 (1984) reported that short peptide aldehydes are renin inhibitors. While the molecular weight of the described compounds are indeed substantially lower than those described by Boger, these compounds, possessing a reactive C-terminal aldehyde group, are expected to be unstable in vivo, and thus their usefulness as therapeutic agents is compromised. The glycols of the present invention are of comparable molecular weight but contain no such therapeutically detrimental moiety as an aldehyde group; the active core is a physiologically compatible 1,2 diol group such as that found in the natural product glycerine.
European Patent Application 128762A discloses dipeptide and tripeptide renin inhibitors containing glycols, however, the aminoglycols of the present invention are chemically distinct from those disclosed in this application.
For other articles describing previous efforts to devise renin inhibitors, see Marshall, Federation Proc. 35: 2494-2501, 1976; Burton et al., Proc. Natl. Acad. Sci. USA 77: 5476-5479, Sept. 1980; Suketa et al., Biochemistry 14: 3188, 1975; Swales, Pharmac. Ther. 7: 173-201, 1979; Kokubu et al., Nature 217: 456-457, Feb. 3, 1968; Matsushita et al., J. Antiobiotics 28: 1016-1018, December 1975; Lazar et al., Biochem. Pharma: 23: 2776-2778, 1974; Miller et al., Biochem. Pharma. 21: 2941-2944 1972; Haber, Clinical Science 59: 7s-19s, 1980; Rich et al., J. Org. Chem. 43: 3624, 1978, J. Med. Chem. 23: 27, 1980; and especially Haber, Clin. and Exper. Hyper., A5(7&8), 1193 (1983).